Mechanism of shortened action potential duration in Na^sup +^-Ca^sup 2+^ exchanger knockout mice

In cardiac-specific ... exchanger (NCX) knockout (KO) mice, the ventricular action potential (AP) is shortened. The shortening of the AP, as well as a decrease of the L-type ... current (...), provides a critical mechanism for the maintenance of ... homeostasis and contractility in the absence of NCX (Pott C, Philipson KD, Goldhaber JI. Excitation-contraction coupling in ... exchanger knockout mice: reduced transsarcolemmal ... flux. Circ Res 97: 1288-1295, 2005). To investigate the mechanism that underlies the accelerated AP repolarization, we recorded the transient outward current (...) in patch-clamped myocytes isolated from wild-type (WT) and NCX KO mice. Peak ... was increased by 78% and decay kinetics were slowed in KO vs. WT. Consistent with increased ..., ECGs from KO mice exhibited shortened QT intervals. Expression of the ...-generating ... channel subunit Kv4.2 and the ... channel interacting protein was increased in KO. We used a computer model of the murine AP (Bondarenko VE, Szigeti GP, Bett GC, Kim SJ, and Rasmusson RL. Computer model of action potential of mouse ventricular myocytes. Am J Physiol Heart Circ Physiol 287: 1378-1403, 2004) to determine the relative contributions of increased ..., reduced ... and reduced NCX current (...) on the shape and kinetics of the AP. Reduction of ... and elimination of ... had relatively small effects on the duration of the AP in the computer model. In contrast, AP repolarization was substantially accelerated when ... was increased in the computer model. Thus, the increase in ..., and not the reduction of ... or ... is likely to be the major mechanism of AP shortening in KO myocytes. The upregulation of ... may comprise an important regulatory mechanism to limit ... influx via a reduction of AP duration, thus preventing ... overload in situations of reduced myocyte Ca^sup 2+^ extrusion capacity. (ProQuest Information and Learning: ... denotes formulae/symbols omitted.)